• Han Gao, Xianghui Huang, Weicheng Chen, Zhiyu Feng, Zhengshan Zhao, Ping Li, Chaozhong Tan, Jinxin Wang, Quannan Zhuang, Yuan Gao, Shaojie Min, Qinyu Yao, Maoxiang Qian, Xiaojing Ma, Feizhen Wu, Weili Yan, Wei Sheng, and Guoying Huang.
• Children's Hospital of Fudan University, Shanghai 201102, China.
• Chin. Med. J. 2024 Aug 5; 137 (15): 182318341823-1834.

BackgroundHeterotaxy (HTX) is a thoracoabdominal organ anomaly syndrome and commonly accompanied by congenital heart disease (CHD). The aim of this study was to analyze rare copy number variations (CNVs) in a HTX/CHD cohort and to examine the potential mechanisms contributing to HTX/CHD.MethodsChromosome microarray analysis was used to identify rare CNVs in a cohort of 120 unrelated HTX/CHD patients, and available samples from parents were used to confirm the inheritance pattern. Potential candidate genes in CNVs region were prioritized via the DECIPHER database, and PNPLA4 was identified as the leading candidate gene. To validate, we generated PNPLA4 -overexpressing human induced pluripotent stem cell lines as well as pnpla4 -overexpressing zebrafish model, followed by a series of transcriptomic, biochemical and cellular analyses.ResultsSeventeen rare CNVs were identified in 15 of the 120 HTX/CHD patients (12.5%). Xp22.31 duplication was one of the inherited CNVs identified in this HTX/CHD cohort, and PNPLA4 in the Xp22.31 was a candidate gene associated with HTX/CHD. PNPLA4 is expressed in the lateral plate mesoderm, which is known to be critical for left/right embryonic patterning as well as cardiomyocyte differentiation, and in the neural crest cell lineage. Through a series of in vivo and in vitro analyses at the molecular and cellular levels, we revealed that the biological function of PNPLA4 is importantly involved in the primary cilia formation and function via its regulation of energy metabolism and mitochondria-mediated ATP production.ConclusionsOur findings demonstrated a significant association between CNVs and HTX/CHD. Our data strongly suggested that an increased genetic dose of PNPLA4 due to Xp22.31 duplication is a disease-causing risk factor for HTX/CHD.Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

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